683-58-9Relevant articles and documents
New analogues of epiboxidine incorporating the 4,5-dihydroisoxazole nucleus: Synthesis, binding affinity at neuronal nicotinic acetylcholine receptors, and molecular modeling investigations
Dallanoce, Clelia,Magrone, Pietro,Bazza, Paola,Grazioso, Giovanni,Rizzi, Luca,Riganti, Loredana,Gotti, Cecilia,Clementi, Francesco,Frydenvang, Karla,De Amici, Marco
, p. 244 - 259 (2009)
A group of novel 4,5-dihydro-3-methylisoxazolyl derivatives, structurally related to epiboxidine (= 1R,4S,6S)-6-(3-methylisoxazol-5-yl)-7-azabicyclo[2.2.1]heptane), was prepared via 1,3-dipolar cyclo-addition of acetonitrile oxide to different olefins. Target compounds 1a and 1b, 2a and 2b, 3, 4, and 5 were tested for affinity at neuronal nicotinic heteromeric (α4β2) and homomeric (α7) acetylcholine receptors. Notably, diastereoisomers 1a and 1b were characterized by a massive drop of the affinity at the α4β2 subtypes (Ki values spanning the range 4.3-126 μM), when compared with that of epiboxidine (Ki= 0.6 nM). Therefore, the replacement of the 3-methylisoxazole ring of epiboxidine with the 4,5-dihydro-3-methylisoxazole nucleus is detrimental for the affinity at α4β2 receptors. A comparable lack of affinity/selectivity for the two nAChR subtypes under study was evidenced for the remaining epiboxidine-related dihydroisoxazole derivatives 2a and 2b, and 3-5. Diastereoisomers 1a and 1b, and spirocyclic derivative 3 were docked into molecular models of the receptor subtypes under study, and their binding mode was compared with that of reference ligands endowed with high binding affinity.
Discovery and preclinical development of AR453588 as an anti-diabetic glucokinase activator
Aicher, Thomas D.,Baer, Brian R.,Boyd, Steven A.,Chicarelli, Mark D.,Condroski, Kevin R.,DeWolf, Walter E.,Fischer, John,Frank, Michele,Hingorani, Gary P.,Hinklin, Ronald J.,Lee, Patrice A.,Neitzel, Nickolas A.,Pratt, Scott A.,Singh, Ajay,Sullivan, Francis X.,Turner, Timothy,Voegtli, Walter C.,Wallace, Eli M.,Williams, Lance
supporting information, (2019/12/24)
Glucose flux through glucokinase (GK) controls insulin release from the pancreas in response to high levels of glucose. Flux through GK is also responsible for reducing hepatic glucose output. Since many individuals with type 2 diabetes appear to have an inadequacy or defect in one or both of these processes, identifying compounds that can activate GK could provide a therapeutic benefit. Herein we report the further structure activity studies of a novel series of glucokinase activators (GKA). These studies led to the identification of pyridine 72 as a potent GKA that lowered post-prandial glucose in normal C57BL/6J mice, and after 14d dosing in ob/ob mice.
BRIDGED TRICYCLIC CARBAMOYLPYRIDONE COMPOUNDS AND THEIR PHARMACEUTICAL USE
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Paragraph 0755, (2020/10/20)
Compounds for use in treating or preventing human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2, L, W1, W2, X, Y, and Z are as defined herein. Methods associated with the preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.
